title: Secreted Bacillus anthracis proteases target the host fibrinolytic system.
abstract: The fibrinolytic system is often the target for pathogenic bacteria, resulting in increased fibrinolysis, bacterial dissemination, and inflammation. The purpose of this study was to explore whether proteases NprB and InhA secreted by Bacillus anthracis could activate the host's fibrinolytic system. NprB efficiently activated human pro-urokinase plasminogen activator (pro-uPA), a key protein in the fibrinolytic cascade. Conversely, InhA had little effect on pro-uPA. Plasminogen activator inhibitors (PAI)-1, 2 and the uPA receptor were also targets for NprB in vitro. InhA efficiently degraded the thrombin-activatable fibrinolysis inhibitor (TAFI) in vitro. Mice infected with B. anthracis showed a significant decrease in blood TAFI levels. In another mouse experiment, animals infected with isogenic inhA deletion mutants restored TAFI levels, while the levels in the parent strain decreased. We propose that NprB and InhA may contribute to the activation of the fibrinolytic system in anthrax infection.
authors.affiliation: National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA, USA. mchung3@gmu.edu
authors.forename: Myung-Chul
authors.initials: MC
authors.lastname: Chung
authors.forename: Shelley C
authors.initials: SC
authors.lastname: Jorgensen
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Tonry
authors.forename: Fatah
authors.initials: F
authors.lastname: Kashanchi
authors.forename: Charles
authors.initials: C
authors.lastname: Bailey
authors.forename: Serguei
authors.initials: S
authors.lastname: Popov
mesh_terms: D000818:Animals; D000881:Anthrax / Q000382:microbiology / Q000473:pathology; D001408:Bacillus anthracis / Q000201:enzymology*; D025901:Carboxypeptidase B2 / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005342:Fibrinolysis; D006801:Humans; D051379:Mice; D008811:Mice, Inbred DBA; D010447:Peptide Hydrolases / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D017396:Plasminogen Activator Inhibitor 2 / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012376:Rodent Diseases / Q000382:microbiology / Q000473:pathology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D017396:Plasminogen Activator Inhibitor 2; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins; C051321:SERPINE1 protein, human; D010447:Peptide Hydrolases; D025901:Carboxypeptidase B2; D014568:Urokinase-Type Plasminogen Activator; C067551:saruplase